tbuckley/cabot-search huggingface dataset:
Metronomic systemic PCm (paclitaxel, carboplatin + metronomic) neoadjuvant chemotherapy in head and neck cancer.
Authors: Gunjesh Kumar Singh, Kumar Prabhash, Vijay Maruti Patil, Vanita Noronha, Amit Joshi, Nandini Sharrel Menon, Pragya Singh, Burhanuddin Qayyumi, Ravikant Singh
Journal: Journal of Clinical Oncology (2022)

e18073 Background: Neoadjuvant chemotherapy (NACT) in head and neck cancers (HNC) with taxane, platinum, 5-FU (TPF) regimen is both toxic as well as difficult to use in resource-constrained settings. We used a novel combination of weekly chemotherapy and oral metronomic chemotherapy (OMCT) and assessed the efficacy and safety of this combination as NACT in locally advanced HNC patients. Methods: This is a retrospective analysis of prospectively maintained data. 56 patients with technically unresectable HNC received NACT with paclitaxel (80mg/m2) plus carboplatin (AUC2) - weekly schedule and OMCT (methotrexate 9mg/m2 once a week, celecoxib 200mg twice daily, and erlotinib 150mg once daily) - PCm regimen. Patients were assessed clinically and radiologically after a minimum of six cycles for resectability. The radiological response was evaluated as per RECIST 1.1. We report the response rate, resectability, survival, and tolerance of this NACT regimen. Results: The median age of the patients was 41 years. Fifty-two patients (92.9%) were male. Buccal mucosa (60.7%) and oral tongue (17.9%) were the commonest sites of primary seen followed by alveolus (10.7%), the floor of mouth (5.4%), and larynx (5.4%). AJCC 2017 stage IVA and IVB disease were present in 64.3% and 35.7% of patients respectively. Edema up to zygoma (44.6%), high ITF involvement (19.7%), technically unresectable nodal disease (16.1%) and disease reaching up to vallecula (12.5%), or hyoid bone (5.4%), and nodal encasement (180-270 degree) of the internal carotid artery (1.8%) were the reasons for technical unresectability. The median number of NACT administered was six. The tumor showed partial response in 54 (96.4%) patients, 2 (3.6%) patients had stable disease and none of the patients had tumor progression. Surgery was planned in 47 (83.9%) patients after NACT, however due to logistic issues only 35 (62.5%) patients could undergo surgery. Pathological complete response was seen in 27 (48.21%) patients. After a median follow-up of 7.36 months, median PFS was not reached in the whole cohort and surgery group of patients, whereas it was 5.23 (95% CI, 4.08 -6.38) months in the non-surgery group. Median OS was not reached in our cohort. Common grade 3/4 toxicities (CTCAE 5.0) observed were oral mucositis in 6 (10.7%) patients, diarrhea in 4 (7.1%), and febrile neutropenia in 1 (1.7%) patients. Conclusions: Weekly scheduled PCm is an efficacious and well-tolerated regimen and can easily be administered in resource-constrained settings.
LGG-05. A Nine-month-old Boy with Regression of Milestones and Severe Constipation: An Unusual Case of a Spinal Pilocytic Astrocytoma
Authors: Rachel Offenbacher, Andrew Kobets, Nagma Dalvi, Kevin Hsu, Steven Chin, Matija Snuderl, Adam Levy, Allison Martin
Journal: Neuro-Oncology (2022)

Abstract Pilocytic astrocytoma (PA), a World Health Organization Grade 1 tumor, is the most common brain tumor in children between 5 and 14 years of age and the second most common in children younger than 5 and older than 14. Although classical to the cerebellum and hypothalamic regions, it can also arise in the spinal cord. A nine-month-old boy with a history of torticollis and plagiocephaly presented with a four-month history of regression of milestones, irritability and severe constipation. He was noted to have flaccid paralysis of the lower extremities and decreased reflexes. Ophthalmologic exam was significant for papilledema and magnetic resonance imaging of the spine were notable for a large infiltrative heterogeneously enhancing lesion extending from T4 to the conus containing several loculated intratumoral cysts with abnormal enhancing margins from T4 to T8. He underwent embolization and complete tumor resection. Post-op MRI was notable for an oval shape non-enhancing soft tissue measuring 8 mm along the medial wall of the left lateral ventricle. Comprehensive tumor molecular profiling on the resected spinal tumor tissue (Caris MI), revealed an NTRK1 fusion, MEF2D-NTRK1, Exon 12. Larotrectinib was initiated at 100mg/m2 per dose oral twice daily to target this specific mutation. Follow up imaging 3 months later showed decrease in the size of intracranial lesions. To date, there is only one other case report demonstrating intracranial metastasis from a spinal PA. Due to the size of his spinal lesion, we believe this was his primary site; however, as described in the literature, there is no definitive way to determine the initiating lesion. The use of comprehensive molecular profiling facilitated the discovery of a targetable oncogenic mutation that changed initial management. To the best of our knowledge there has been only one other case report describing this specific fusion in a pediatric spinal CNS tumor.
Adagrasib in Non–Small-Cell Lung Cancer Harboring a <i> KRAS <sup>G12C</sup> </i> Mutation
Authors: Pasi A. Jänne, Gregory J. Riely, Shirish M. Gadgeel, Rebecca S. Heist, Sai-Hong I. Ou, Jose M. Pacheco, Melissa L. Johnson, Joshua K. Sabari, Konstantinos Leventakos, Edwin Yau, Lyudmila Bazhenova, Marcelo V. Negrao, Nathan A. Pennell, Jun Zhang, Kenna Anderes, Hirak Der-Torossian, Thian Kheoh, Karen Velastegui, Xiaohong Yan, James G. Christensen, Richard C. Chao, Alexander I. Spira
Journal: New England Journal of Medicine (2022)

Adagrasib, a KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib showed clinical activity and had an acceptable adverse-event profile in the phase 1–1b part of the KRYSTAL-1 phase 1–2 study.
Five-year survival stratification using “the Cancer Of the Bladder Risk Assessment” (COBRA) score for micropapillary and sarcomatoid urothelial carcinoma of the bladder variants.
Authors: Carlos Rivera, Iktej Singh Jabbal, Marita Yaghi, Diana Saravia, Nicolas Muruve, Barbara Ercole, Tiffany L. George, Zeina A. Nahleh, Rafael Eduardo Arteta-Bulos
Journal: Journal of Clinical Oncology (2022)

e16534 Background: The Cancer of the Bladder Risk Assessment (COBRA) score is a validated risk stratification tool for patients with urothelial carcinoma of the bladder (UCB) after cystectomy. Radical cystectomy with or without neoadjuvant chemotherapy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). Lymph node density and the presence of positive lymph nodes have been demonstrated to be critical prognostic tools. Our goal was to evaluate 5-year overall survival (OS) on UCB variants: micropapillary and sarcomatoid, stratified by COBRA score and the presence of lymph nodes. Methods: We sampled the National Cancer Database (NCDB) for bladder cancer patients diagnosed with de novo micropapillary and sarcomatoid UCB between 2004 and 2018 and treated with radical cystectomy. 5-year Kaplan-Meier survival plots were utilized to assess OS differences amongst different COBRA score groups and stratified by the presence of lymph nodes (LNs). A multivariable Cox regression model was used to compare hazard ratios, adjusting for significantly unbalanced factors. A p-value &lt; 0.05 was considered statistically significant. Results: A total of 1382 patients met the inclusion criteria. The average age was 68.10 + 10.31 years. 75% were male. Micropapillary represented 50.1% of selected histologies, followed by 49.5% sarcomatoid. For all combined histologies, 5-year OS percentage for patients with cystectomy and stratified by COBRA score (0-7) were 66% COBRA 0, 54% COBRA 1, 34% COBRA 2, 29% COBRA3, 15% COBRA &gt; 4) (p &lt; 0.001). 5-year OS for patients with cystectomy stratified by LN status was 54% for LN negative and 24% for LN positive (p &lt; 0.001). Substratification of the cohort according to the presence of LNs and COBRA score have shown a numerical drop in 5-year survival and a notable decrease in median survival amongst compared groups. The risk of death was almost 5 times higher in patients with a high COBRA score (&gt; 4) than in patients with a COBRA score of 0 (HR = 5.15, p &lt; 0.001). Conclusions: COBRA score could contribute to clinical decision-making as a risk stratification tool for patients with UCB variants, micropapillary and sarcomatoid. 5-year OS decreases with higher COBRA scores, and LN status plays a major role in 5-year OS for these two UCB variants.[Table: see text]
Tumor-stroma interaction in cervical cancer: The prognostic importance of desmoplasia.
Authors: Benjamin Wolf, Lars-Christian Horn, Michael Höckel, Bahriye Aktas
Journal: Journal of Clinical Oncology (2022)

e17519 Background: During tumor growth, cancer cells can induce the formation of new extracellular matrix, mainly by activating peritumoral fibroblasts. This stromal reconfiguration has been termed desmoplasia. In pancreatic and ovarian cancer models, targeting desmoplasia therapeutically to normalize the microenvironment has recently shown promising results. We investigated the frequency and prognostic relevance of peritumoral desmoplasia, as well as its association with other prognostic factors such as lymph node involvement and parametrial tumor extension in cervical cancer patients. Methods: A retrospective cohort study based on data from the prospective monocentric observational Leipzig School Mesometrial Resection study was conducted. Cervical cancer patients staged IB1 to IVA according to the Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) who underwent primary surgery between 1999 and 2017 were included. Information regarding desmoplastic tumor reaction was retrospectively retrieved from the pathology reports. All other data had been collected prospectively during the trial period. Using non-parametric tests, we calculated the association of peritumoral desmoplasia with other common risk factors. To determine the prognostic significance of desmoplasia, we used the Kaplan-Meier estimator and performed multivariable Cox-regression modelling. Results: Overall, 355 patients were included. Desmoplasia was present in 298 cases and was associated with a significantly higher likelihood of lymphovascular space involvement (odds ratio [OR] 2.7, 95% confidence interval [CI] 1.4 – 5.1, p = 0.001) and venous infiltration (OR 5.1, 95%-CI 1.3 – 44.9, p = 0.01). Lymph node metastasis was more common in patients with desmoplasia (OR 2.4, 95%-CI 1.2 – 5.0, p = 0.01), as was parametrial involvement (OR 3.5, 95%-CI 1.7 – 7.9, p = 0.0002). Interestingly, the presence of desmoplasia was not associated with larger tumor size. Patients with desmoplastic tissue reaction were significantly older than those without desmoplasia (median 41 years [inter quartile range 34 – 51] vs. 47 years [IQR 39-56], p = 0.009). These prognostically negative parameters in patients with desmoplastic disease translated into inferior overall (94.5% vs 80.5%, OR 3.9 [95%-CI 1.2 – 12.5], p = 0.02) and recurrence-free survival (86.8% vs. 74.2%, OR 2.3 [95%-CI 1.0 – 4.9], p = 0.04). A multivariable Cox-regression model including tumor size, patient age, and nodal status indicated that desmoplasia was an independent risk factor for overall death (OR 4.2, 95%-CI 1.03 – 17.5, p = 0.04). Conclusions: Desmoplastic stromal remodeling is associated with a more aggressive phenotype of cervical cancer and inferior survival. Targeting desmoplasia, especially in advanced disease when surgical treatment is not feasible, might be a promising treatment approach in the future.
Effectiveness of chemotherapy on prognosis of elderly breast cancer: A retrospective cohort study based on SEER database.
Authors: Yunhao Wu, Yana Qi, Jiqiao Yang, Ruoning Yang, Ruixian Chen, Ya Huang, Weijing Liu, Xin Zhao, Tao He, Shan Lu, Zhoukai Fu, Zhu Wang, Qintong Li, Xin Sun, Jie Chen
Journal: Journal of Clinical Oncology (2022)

e12525 Background: The estimated population of breast cancer older than 70 years is over 80,000 new onset cases in 2019 and keep increasing. Currently, the proportion of standard chemotherapy for elderly patients was much lower than that for young patients, due to shorter life expectancy, more comorbidities, and concerns over increased toxicities and reduced tolerance. Till now, few evidences from clinical trials could support the use of chemotherapy for elderly patients, as also indicated by current guidelines for adjuvant chemotherapy. The effectiveness of chemotherapy for elderly breast cancer remains to be further verified. Methods: We identified 75,525 female breast cancer patients aged 70 years and older in the Surveillance, Epidemiology, and End Results (SEER) database from January 1, 2010, to December 31, 2016, and excluded those patients with secondary, metastatic, or bilateral breast cancer, not confirmed by pathology, lacking of key information, dead or loss to follow-up in 6 months after diagnosis. Propensity score matching (PSM) (PSM ratio: 1:1, caliper: 0.2* standard deviation of propensity score) was applied to construct balanced cohorts with or without chemotherapy based on demographic and pathophysiological characteristics. Kaplan-Meier analysis, multivariable Cox proportional model, and subgroup analysis were performed to evaluate the effectiveness of chemotherapy on overall survival (OS) and breast cancer-specific survival (BCSS). Results: A total of 33,177 eligible patients were included, of them, 5273 (15.89%) received chemotherapy. Through PSM, 8360 patients were successfully matched and almost reached balances between groups. In matched dataset, patients receiving chemotherapy exhibited a better prognosis on OS and BCSS (the 5-year survival rate, OS: 0.80 [0.78-0.82] with chemotherapy vs. 0.71[0.69-0.73] control; BCSS: 0.88 [0.87-0.89] with chemotherapy vs. 0.85 [0.84-0.86]; both log-rank test, P &lt; 0.001); in multivariable Cox analysis, chemotherapy was associated with a 35% and 21% risk reduction on OS (HR [95%CI]: 0.65[0.59-0.72]) and BCSS (0.79[0.69-0.91]), respectively. Furthermore, subgroups with HER-2 positive, or more lymph nodes involved, were inclined to benefit more from chemotherapy. Conclusions: Our study provided additional evidences that chemotherapy may improve the prognosis of elderly breast cancer, especially for those subpopulations benefit more from chemotherapy treatment.
TBIO-03. Angiogenesis in Pituitary Adenoma
Authors: Daizo Yoshida, Ryutaro Nomura, Akira Teramoto
Journal: Neuro-Oncology (2022)

Abstract The role of angiogenesis in pituitary tumor development used to be questioned, since pituitary tumors have been usually found to be less vascularized than the normal pituitary tissue. Nevertheless, a significantly higher degree of vasculature has been shown in invasive or macropituitary prolactinomas when compared to nonin- vasive and microprolactinomas. We should know VEGF was found firstly in pituitary anterior lobe, then tumor angiogenesis must occur. Meanwhile the vascular arrange- ment raised by VEGF is irregular, that sometimes lead to pituitary apoplexy. In this chapter, hypoxia inducible factors (HIF), transcription factors regulating expression of several genes related to oxygen homeostasis are in response to hypoxic stress. We focus on tumor angiogenesis regulated by the signaling cascade in tumor angiogenesis in pituitary tumor.
Optimal timing and interval of imaging for metastatic breast cancer.
Authors: Shruti Rajesh Patel, Haruka Itakura, George W. Sledge
Journal: Journal of Clinical Oncology (2022)

1106 Background: Breast cancer is a family of diseases with varying disease trajectories based on intrinsic biology of the tumor. The time of progression varies across &amp; within subtypes, and with increasing rates of drug resistance depending on prior therapeutic exposure. There is no strong consensus about optimal surveillance and routine imaging in patients with metastatic breast cancer (mBC), but many oncologists report that monitoring strategies are based on strategies used in clinical trials. Methods: We reviewed 17 prior Phase III studies that led to FDA approval in mBC. We reviewed 8 studies for ER+ mBC, 5 studies for HER2+ mBC, 2 studies for triple negative (TNBC) mBC, and 2 studies for BRCA+ mBC. We calculated rates of progression or death (POD) per month for the first year on therapy using data from survival analysis tables and compared them across the different types and lines of therapy. Results: Risk of progression in mBC varies based on receptor status and line of therapy (Table). There was a significant difference in POD rates between ER+ therapies compared with all other disease types (HER2+, TNBC, BRCA) (p = 0.012). Patients with TNBC or receiving PARP inhibitors or later line HER2 therapies had higher POD rates than those with ER+ breast cancer or receiving first line HER2 therapy (6.9% vs 4.1% per month; p = 0.0004). No significant difference was seen in the monitoring frequency between ER+ and HER2+ disease (p = 0.39). Conclusions: These data suggest that shorter interval imaging should be performed for patients with TNBC or receiving PARP inhibitors or later line HER2 therapies. Surveillance imaging for patients with mBC should be based on disease biology, number of prior regimens, time since initiation of therapy, and regimen efficacy. Current imaging recommendations are not data-based and do not adjust for new agents that have been approved. Oncologists should integrate these into individualized estimates to determine optimum frequency of imaging in clinical practice and research. [Table: see text]
Spatiotemporal Regulation of a Single Adaptively Evolving<i>Trans</i>-Regulatory Element Contributes to Spermatogenetic Expression Divergence in<i>Drosophila</i>
Authors: Yumei Huang, Rui Shang, Guang-An Lu, Weishun Zeng, Chenglong Huang, Chuangchao Zou, Tian Tang
Journal: Molecular Biology and Evolution (2022)

Abstract Due to extensive pleiotropy, trans-acting elements are often thought to be evolutionarily constrained. While the impact of trans-acting elements on gene expression evolution has been extensively studied, relatively little is understood about the contribution of a single trans regulator to interspecific expression and phenotypic divergence. Here, we disentangle the effects of genomic context and miR-983, an adaptively evolving young microRNA, on expression divergence between Drosophila melanogaster and D. simulans. We show miR-983 effects promote interspecific expression divergence in testis despite its antagonism with the often-predominant context effects. Single-cyst RNA-seq reveals that distinct sets of genes gain and lose miR-983 influence under disruptive or diversifying selection at different stages of spermatogenesis, potentially helping minimize antagonistic pleiotropy. At the round spermatid stage, the effects of miR-983 are weak and distributed, coincident with the transcriptome undergoing drastic expression changes. Knocking out miR-983 causes reduced sperm length with increased within-individual variation in D. melanogaster but not in D. simulans, and the D. melanogaster knockout also exhibits compromised sperm defense ability. Our results provide empirical evidence for the resolution of antagonistic pleiotropy and also have broad implications for the function and evolution of new trans regulators.
External validation of the SPARE nephrometric index as a predictor of early complications after partial nephrectomy
Authors: M. Santiago Gonzalez, V. Gómez Dos Santos, V. Hevia Palacios, C. Mínguez Ojeda, M. Mata Alcaraz, S. Álvarez Rodríguez, J. Lorca Álvaro, V. Díez Nicolás, F.J. Burgos Revilla
Journal: European Urology (2022)
Rare Germline Variants Are Associated with Rapid Biochemical Recurrence After Radical Prostate Cancer Treatment: A Pan Prostate Cancer Group Study
Authors: Daniel Burns, Ezequiel Anokian, Edward J. Saunders, Robert G. Bristow, Michael Fraser, Jüri Reimand, Thorsten Schlomm, Guido Sauter, Benedikt Brors, Jan Korbel, Joachim Weischenfeldt, Sebastian M. Waszak, Niall M. Corcoran, Chol-Hee Jung, Bernard J. Pope, Chris M. Hovens, Géraldine Cancel-Tassin, Olivier Cussenot, Massimo Loda, Chris Sander, Vanessa M. Hayes, Karina Dalsgaard Sorensen, Yong-Jie Lu, Freddie C. Hamdy, Christopher S. Foster, Vincent Gnanapragasam, Adam Butler, Andy G. Lynch, Charlie E. Massie, Dan J. Woodcock, Colin S. Cooper, David C. Wedge, Daniel S. Brewer, Zsofia Kote-Jarai, Rosalind A. Eeles
Journal: European Urology (2022)

Germline variants explain more than a third of prostate cancer (PrCa) risk, but very few associations have been identified between heritable factors and clinical progression.To find rare germline variants that predict time to biochemical recurrence (BCR) after radical treatment in men with PrCa and understand the genetic factors associated with such progression.Whole-genome sequencing data from blood DNA were analysed for 850 PrCa patients with radical treatment from the Pan Prostate Cancer Group (PPCG) consortium from the UK, Canada, Germany, Australia, and France. Findings were validated using 383 patients from The Cancer Genome Atlas (TCGA) dataset.A total of 15,822 rare (MAF <1%) predicted-deleterious coding germline mutations were identified. Optimal multifactor and univariate Cox regression models were built to predict time to BCR after radical treatment, using germline variants grouped by functionally annotated gene sets. Models were tested for robustness using bootstrap resampling.Optimal Cox regression multifactor models showed that rare predicted-deleterious germline variants in "Hallmark" gene sets were consistently associated with altered time to BCR. Three gene sets had a statistically significant association with risk-elevated outcome when modelling all samples: PI3K/AKT/mTOR, Inflammatory response, and KRAS signalling (up). PI3K/AKT/mTOR and KRAS signalling (up) were also associated among patients with higher-grade cancer, as were Pancreas-beta cells, TNFA signalling via NKFB, and Hypoxia, the latter of which was validated in the independent TCGA dataset.We demonstrate for the first time that rare deleterious coding germline variants robustly associate with time to BCR after radical treatment, including cohort-independent validation. Our findings suggest that germline testing at diagnosis could aid clinical decisions by stratifying patients for differential clinical management.Prostate cancer patients with particular genetic mutations have a higher chance of relapsing after initial radical treatment, potentially providing opportunities to identify patients who might need additional treatments earlier.